The inability to acquire fully protective immunity against Plasmodium is a chief obstacle to malaria control. High levels of inflammatory cytokines can inhibit memory T cell development in model systems. Notably, all Plasmodia species have been found to encode an ortholog of the upstream inflammatory cytokine, macrophage migration inhibitory factor (MIF). Plasmodium MIF (PMIF) upregulates inflammatory responses during infection, leading to enhanced activation-induced T cell apoptosis and fewer antigen- experienced CD4 T cells that become memory cells. This finding suggests that Plasmodia actively interfere with the generation of malaria-specific memory CD4 T cells to enable parasite persistence and transmission. To better understand ineffective immunity to malaria and to provide a foundation for better vaccines, we will determine the specific role of PMIF in the anti-malarial immune response in three Specific Aims, as follow: Aim 1. Define the Molecular Basis for the Pro-inflammatory Activation of the Immune Response by Plasmodium-encoded MIF (PMIF). We hypothesize that PMIF increases inflammatory responses by activating the host MIF receptor. We will define shared and unique signaling properties of PMIF versus host MIF and examine the role of the conserved N-terminal region, which mediates binding to the MIF receptor. We will investigate the action of PMIF on Toll-like and NOD-like receptor activation pathways, and we will validate our observations in mice infected with a P. berghei ANKA strain lacking its mif gene. Aim 2. Define the Cellular and Molecular Basis for the Suppression of the Anti-malarial Adaptive Immune Response by PMIF. We hypothesize that a strong pro-inflammatory environment during malaria infection favors the generation of terminal effector CD4 T cells at the expense of protective, memory precursor CD4 T cells. We will elucidate the cytokine and signaling pathways responsible for this response, examine the role of T follicular helper cells (TFH) and their ability to provide help to B and to T cells, and analyze T cell exhaustion. Aim 3. Evaluate the Therapeutic Potential of PMIF Neutralization in Malaria. We will explore the impact of neutralization of PMIF in mouse models of blood-stage and sporozoite infection. Our approach will include immunization with PMIF by a novel self-amplifying RNA vaccine and a pharmacologic strategy based on our discovery of a selective, small molecule inhibitor of PMIF. These studies will provide insight into how Plasmodia direct the host inflammatory response to interfere with protective immunity and suggest new strategies for therapeutic immunomodulation and vaccine development. Conclusions from this work may be generalized to other parasite pathogens, such as Leishmania, Ancyclostoma, and Brugia, which produce their own closely homologous MIF proteins.